Effect of ω-conotoxin MVIIA and Phα1β on paclitaxel-induced acute and chronic pain

Abstract

The treatment with the chemotherapeutic agent paclitaxel produces a painful peripheral neuropathy, and is associated with an acute pain syndrome in a clinically significant number of patients. However, no standard therapy has been established to manage the acute pain or the chronic neuropathic pain related to paclitaxel. In the present study, we evaluated the analgesic potential of two N-type voltage-gated calcium channel (VGCC) blockers, ω-conotoxin MVIIA and Phα1β, on acute and chronic pain induced by paclitaxel. Adult male rats were treated with four intraperitoneal injections of paclitaxel (1+1+1+1mg/kg, in alternate days) and the development of mechanical hyperalgesia was evaluated 24h (acute painful stage) or 15days (chronic painful stage) after the first paclitaxel injection. Not all animals showed mechanical hyperalgesia 24h after the first paclitaxel injection, but those that showed developed a more intense mechanical hyperalgesia at the chronic painful stage. Intrathecal administration (i.t.) of ω-conotoxin MVIIA (3-300pmol/site) or Phα1β (10-300pmol/site) reduced the mechanical hyperalgesia either at the acute or at the chronic painful stage induced by paclitaxel. When administered at the acute painful stage, ω-conotoxin MVIIA (300pmol/site, i.t.) and Phα1β (300pmol/site, i.t.) prevented the worsening of chronic mechanical hyperalgesia. Furthermore, Phα1β (30-300pmol/site, i.t.) elicited less adverse effects than ω-conotoxin MVIIA (10-300 pmol/site, i.t.). Taken together, our data evidence the involvement of N-type VGCC in pain sensitization induced by paclitaxel and point out the potential of Phα1β as a safer alternative than ω-conotoxin MVIIA to treat the pain related to paclitaxel.

Antinociceptive activity of transient receptor potential channel TRPV1, TRPA1, and TRPM8 antagonists in neurogenic and neuropathic pain models in mice

“…Full hypersensitivity is usually observed 7-14 d after a single injection of paclitaxel (Andoh et al, 2013;Rigo et al, 2013). We have shown that TRPM8 is involved in cold hyperalgesia in mice treated with paclitaxel.…”

Calcium Channels and Associated Receptors in Malignant Brain Tumor Therapy

“…As in other kinds of cancer, brain tumors often present genetic mutations in tumor suppressors and oncogenes; surprisingly, alterations in ion channel/transporter activity are linked to up-or down-regulation of these encoding genes in most brain tumor cases (Ransom et al, 2001;Masselli et al, 2012). Furthermore, dysregulation in Ca 21 channel activity in the central nervous system is related to many types of neurologic disorders, including epilepsy (Zamponi et al, 2010), Alzheimer's disease (Amenta et al, 2009), and chronic pain (Rigo et al, 2013a). …”

“…N-and P/Q-type channels blockers are suggested to lead to a clinical improvement of cognitive decline in Alzheimer's patients (Amenta et al, 2009) and to an absence of seizures in epilepsy (Zamponi et al, 2010). Additionally, peptide neurotoxins found in animal venoms have received great interest and have been related to neuropathic pain control (Souza et al, 2008;Rigo et al, 2013a) and the management of cancer-associated pain (Rigo et al, 2013b) in animal models during P/Q-and N-type modulation. Pinheiro et al (2006Pinheiro et al ( , 2009 showed a neuroprotective role for a P/Q-type blocker in an in vitro model of hippocampal ischemia induced by oxygen and glucose deprivation; the neurotoxins prevented neuronal death by inhibition of glutamate release.…”

Chemotherapy-Induced Peripheral Neuropathy

“…With oxaliplatin and paclitaxel, some studies show an acute behavioral effect within 60 min, whereas others observe effects at 24-48 h after initial dosing. [122][123][124][125][126] Longterm effects generally present around 6-10 days following the first drug injection and persist for at least 3-7 weeks following the last injection. 105,127,128 Consistent modalities affected by various chemotherapeutics include mechanical allodynia and cold allodynia.…”